PROJECT SUMMARY For clinical application, a critical remaining hurdle for natural killer (NK) cell-based adoptive transfer immunotherapy (ATI) is the inadequate homing efficiency of ex vivo-expanded effector NKs to the targeted tumor tissues. Another significant obstacle is the lack of well-established non-invasive tools for monitoring NK cell trafficking to tumor tissues. Currently, NK cell-based ATI (NK-ATI) responders or non-responders are identified by changes in serum biomarkers or tumor size, both of which may not occur until weeks or months after therapy initiation. Serial monitoring of NK cell migration to tumors during ATI could alternatively serve as an important early biomarker for timely prediction of longitudinal response, thus affording early adjustments to each individual patient?s therapeutic regimen. Recently, our studies have demonstrated that sorafenib not only inhibits tumor cell proliferation, but also promotes antitumor activity of NKs. Therefore, concurrent administration of sorafenib may be critical for sustained NK activation and cytotoxicity. We have developed biodegradable sorafenib-eluting microsphere (SEM, with a diameter of 492 34 nm; nano-SEM) delivery platforms that significantly increase therapeutic efficacy via image-guided transcatheter IHA delivery. We will develop a new image-guided interventional combination liver cancer immunotherapy approach including a) image-guided transcatheter IHA infusion of NKs directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of nano-SEMs to enhance sorafenib therapeutic efficacy (with minimal side effects) and to strengthen NK antitumor activity.